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As with any food item in Fallout: New Vegas, whiskey's effects—both positive and negative—are altered by the player's Survival skill, including the DT increase provided by the Whiskey Rose perk (see below). With a Survival skill of 100 the player will receive +3 to Charisma and Strength, and -3 to Intelligence, as well as +6 to Damage Threshold if the player has the Whiskey Rose perk.

In Hardcore mode, whiskey will increase the player's level of dehydration. This effect is also affected by the Survival skill, going from +25 at lower levels to +75 with a 100 Survival skill.

Whiskey Rose is a perk provided while Cass is serving as a Companion in the player's party. With this perk the penalty to Intelligence for consuming any type of alcohol is eliminated, as are the effects of alcohol addiction. However, the perk provides an additional bonus when consuming whiskey, providing a temporary 2-6 point increase (based on Survival skill level) to the player's Damage Threshold.

Dixon's whiskey is a variant sold by Freeside merchant Dixon. It provides no Charisma boost and a penalty of 2 to Intelligence, and also has a high 50% addiction rate.

Irradiated whiskey is, as the name indicates, radioactive. It provides the same effects as whiskey with an added 10 rads. It can be found reliably in one place: the Camp Searchlight Fire Station, three bottles located in the kitchen. A fourth bottle may rarely be found in the refrigerator inside Hell's Motel. It can also be found in a small, ruined building east of the mole rat ranch along with some useful loot. Beware of the traps at both entrances.

Both variants do not provide any increase to Damage Threshold when the player has the Whiskey Rose perk, though their penalties to Intelligence are still negated.

Whiskey is needed for the side quest High Times. To help Bill Ronte kick his addiction, the character will need a Speech level of 50 - or a Science level of 50 and Fixer (2), and whiskey (1). If the character's Speech and Science levels are too low, then RadAway (1) will been needed as well as the Fixer (2), and whiskey (1).